lipid-a and Pain

Development of non-infectious subunit vaccines is hampered by a slow pipeline of new adjuvants to replace or enhance alum in part because expectations of safety are high. Transient vaccine side effects are not clinical priorities because they cause no lasting harm and vaccine development has appropriately been focused on avoidance of serious adverse events. As a result, surprisingly little is known about the extent to which side effects caused by a vaccine's reactogencicity are predictive of successful immunization outcomes. Recent clinical studies of pertussis and human papillomavirus vaccines adjuvanted with alum or the TLR4 agonist monophosphoryl lipid A can be used to advance understanding of the relationship between vaccine side effects and immunization outcomes.

Topics: Adjuvants, Immunologic; Alum Compounds; Antibodies, Viral; Diphtheria-Tetanus-acellular Pertussis Vaccines; Drug-Related Side Effects and Adverse Reactions; Humans; Lipid A; Pain; Papillomavirus Infections; Papillomavirus Vaccines; Toll-Like Receptor 4; Treatment Outcome; Vaccination; Whooping Cough

We report the first safety and immunogenicity trial of the Plasmodium falciparum vaccine candidate FMP2.1/AS02A, a recombinant E. coli-expressed protein based upon the apical membrane antigen-1 (AMA-1) of the 3D7 clone formulated with the AS02A adjuvant. We conducted an open-label, staggered-start, dose-escalating Phase I trial in 23 malaria-naïve volunteers who received 8, 20 or 40microg of FMP2.1 in a fixed volume of 0.5mL of AS02A on a 0, 1, and 2 month schedule. Nineteen of 23 volunteers received all three scheduled immunizations. The most frequent solicited local and systemic adverse events associated with immunization were injection site pain (68%) and headache (29%). There were no significant laboratory abnormalities or vaccine-related serious adverse events. All volunteers seroconverted after second immunization as determined by ELISA. Immune sera recognized sporozoites and merozoites by immunofluorescence assay (IFA), and exhibited both growth inhibition and processing inhibition activity against homologous (3D7) asexual stage parasites. Post-immunization, peripheral blood mononuculear cells exhibited FMP2.1-specific lymphoproliferation and IFN-gamma and IL-5 ELISPOT assay responses. This is the first PfAMA-1-based vaccine shown to elicit both potent humoral and cellular immunity in humans. Encouraged by the potential of FMP1/AS02A to target host immunity against PfAMA-1 that is known to be expressed by sporozoite, hepatic and erythrocytic stages, we have initiated field trials of FMP2.1/AS02A in an endemic population in the Republic of Mali.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Animals; Antibodies, Protozoan; Antigens, Protozoan; Cell Line; Cell Proliferation; Cells, Cultured; Cricetinae; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Female; Fluorescent Antibody Technique, Indirect; Headache; Humans; Immunization, Secondary; Interferon-gamma; Interleukin-5; Leukocytes, Mononuclear; Lipid A; Malaria Vaccines; Male; Membrane Proteins; Merozoites; Mesocricetus; Middle Aged; Pain; Plasmodium falciparum; Protozoan Proteins; Saponins; Sporozoites; Vaccines, Synthetic

Although more than 95% of the vaccinated population responds to the currently licensed vaccines against hepatitis B, some groups were found to be low responders. Lipid A as adjuvant, through its ability to activate macrophages, might improve humoral as well as cellular immune response. Therefore we evaluated the profile of a hepatitis B vaccine with the new adjuvant system SBAS4. 150 young adults were enrolled and randomized into three groups: one received the SBAS4 hepatitis B vaccine, the second Engerix-B(TM) and the third a hepatitis B vaccine with an alternative formulation on alum. Vaccinations were at 0 and 6 months. The vaccine was well tolerated. At month 7 all vaccinees were protected but with significant differences in GMTs between groups: 13,271 mIU/ml for the SBAS4 group versus 1203 and 1823 mIU/ml. Hence the hepatitis B vaccine with the new adjuvant system is more immunogenic compared to the other vaccines containing the same antigen and could be suitable for a two dose schedule.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Alum Compounds; Double-Blind Method; Edema; Fatigue; Female; Follow-Up Studies; Headache; Hepatitis B Antibodies; Hepatitis B Vaccines; Humans; Immunity, Cellular; Immunization, Secondary; Lipid A; Lymphocyte Activation; Male; Pain; Safety; Seroepidemiologic Studies; Vaccines, Synthetic

Gram-negative bacterial infections are accompanied by inflammation and somatic or visceral pain. These symptoms are generally attributed to sensitization of nociceptors by inflammatory mediators released by immune cells. Nociceptor sensitization during inflammation occurs through activation of the Toll-like receptor 4 (TLR4) signalling pathway by lipopolysaccharide (LPS), a toxic by-product of bacterial lysis. Here we show that LPS exerts fast, membrane delimited, excitatory actions via TRPA1, a transient receptor potential cation channel that is critical for transducing environmental irritant stimuli into nociceptor activity. Moreover, we find that pain and acute vascular reactions, including neurogenic inflammation (CGRP release) caused by LPS are primarily dependent on TRPA1 channel activation in nociceptive sensory neurons, and develop independently of TLR4 activation. The identification of TRPA1 as a molecular determinant of direct LPS effects on nociceptors offers new insights into the pathogenesis of pain and neurovascular responses during bacterial infections and opens novel avenues for their treatment.

Topics: Animals; Cell Membrane; CHO Cells; Cricetinae; Cricetulus; Escherichia coli; HEK293 Cells; Humans; Ion Channel Gating; Lipid A; Lipopolysaccharides; Membrane Potentials; Mice, Inbred C57BL; Mice, Knockout; Neurogenic Inflammation; Neuropeptides; Nociceptors; Pain; Sensory Receptor Cells; Signal Transduction; Toll-Like Receptor 4; Transient Receptor Potential Channels; TRPA1 Cation Channel